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Respiratory infect

Lectures 27-32

Anatomical characteristics of the URT nasopharynx, larynx, and trachea has normal microflora, filters out particles, lined with mucociliary blanket and ciliated epithelial cells, normal temp 33C, IgA Ab
Characteristics of the LRT bronchi, bronchiloes, alveoli normally sterile, bronchi and bronchioles lined with mucociliary blanket
Alveoli no mucociliary blanket, no ciliated epithelial cells, normally sterile, only particles less than 5 microm can enter, lined with alveolar macrophages, IgG predominant, IgA present, damage interferes with gaseous exchange
Types of RT infections professional/frank invaders: invade healthy RT secondary invaders: invade when damage/deficiency/loss of defenses already exists
Etiology of RT infections extremely variable, affected by many host and microbial factors, single pathogen can be associated with many syndromes or many syndromes can be associated with a single pathogen
underlying mechanisms leading to a secondary RT infection changes ro the RT: epithelial damage, airway function, up regulation and exposure of receptors Alteration of the innate immune response
role of normal microflora protect by occupying receptors, producing antimicrobials
Normal microflora in URT that can be pathogenic corynebacterium, enterobacteriaceae, haemophilus, moraxella, mycoplasma, staph, strep, neisseria, propionibacterium, treponema, candida
Other normal microflora in the URT acinetobacter, actinobacillus, actinomyces, cardiobacteria, eikenella, eubacterium, fusobacterium, kingella, peptostreptococcus, prevotella, prophyromonas, stomatococcus, veillonella
exogenous infection inhalation of droplets (talking, sneezing, coughing), inhalation of dust with fungal spores, self inoculation of eyes, nose, or mouth
endogenous infection due to normal microflora, movement of flora to an unusual location (due to age, predisposing infection), preceding infection causes damage, aspiration of URT flora into unusual location
diagnosis of LRT infections (bacterial) s. pneumoniae, h. influenzae, s. aureus, gram -:gram stain and culture legionella: culture, urine Ag, serology, PCR m and c pneumoniae: serology, culture, PCR bordetella: culture, DFA, serology, PCR mycobacteria: acid fast, culture
diagnosis of LRT infections (viral) influenza: virus isolation respiratory syncitial virus: Ag detection HPIV 1-4: virus isolation adenovirus: Ag detection, PCR
serological tests used for viruses or difficult to culture bacterial pathogens complement fixation, ELISA, latex agglutination
culture media selective and differential used for elimination of normal flora and enable differentiation between bacterial species
specialized media B. pertussis: bordet-gengou C. diptheriae: tinsdale agar, cysteini-tellurite agar
key respiratory pathogens adenoviruses, rhinoviruses, coronaviruses, HPIV, respiratory syncytial viruses, influenzaviruses
Adenovirus family adenoviridae,isocahedral capsids, non-enveloped,fibers on each penton vertices (have affinity for cell surface receptors and hemagglutinin properties), serotype specific Ag=virion surface, trigger neutralizing Ab, linear dsDNA, replicate in nucleus
Phases of viral transcription (adenovirus) Early (E1-4) and late (L1-5)
E1A responsible for modulation of cellular metabolism to increase viral replication. Promotes transformation, deregulates cell growth
E1B cooperates with E1A and p53 to promote oncogenesis and transform via blockage of apoptosis
E2 gene products=E2A and E2B. Necessary for replication of viral DNA, interact with variety of cellular factors
E3 encodes for products that interfere with host defences, prevents TNF alpha and inflammation
E4 facilitates virus messenger RNA metabolism, promotes virus DNA replication and shuttling off of host protein synthesis
L1-5 required for virus production, structural components, encapsidation
Pathogenesis (adenovirus) fiber enables attachment to host cell receptor, penton base inhibits cellular mRNA synthesis&causes cell rounding& tissue damage; interferes with MHC I expression (E3gp 19K binds to heavy chain of MHCI & prevents transport to cell surface), TNF, IFN a& b
epidemiology (adenovirus) widespread, 75% before 14 yrs old, ocular respiratory or GI systems, transmission fecal oral mostly, but respiratory too
outcomes (adenovirus) lytic infection, latent infection in lymphoid tissues
symptoms (adenovirus) cold like: cough, runny nose, pharyngitis, fever, conjunctivitis, pneumonia, acute respiratory disease
differences in age groups (adenoviruses) infants/young children: febrile, undifferentiated URTI children/adults: pharyngoconjunctival fever, follicular conjuntivitis, epidemic keratoconjunctivitis Military: acute respiratory disease young, military, immunocompromised: pneumonia
Rhinoviruses family:picornaviridae, small, isocahedral, non-enveloped, ss+RNA, replicate in cytoplasm
Pathogenesis (rhinoviruses) attachment to ICAM1 via surface canyon/clefts replicate and destroy ciliated epithelium of nasal and tracheal mucosa causes vascular engorgement, increased vascular permeability, increaed mucous production
epidemiology (rhinoviruses) humans=only reservoir, more common and severe in young children, classification by specific neutralization with antisera, many siculating serotypes in one community, transmitted by hand contact, high in close contact environments
control (rhinoviruses) difficult because of many serotypes and lack of cross reactivity therapy based on targeting virus or symptoms
coronaviruses common cold (2nd most common), SARS, family coronaviridae, enveloped, helical nucleocapsid, surface fringe (glycoproteins), ss+ linear RNA, replicate in cytoplasm
Coronavirus S protein spike protein, define tissue tropism, attach to proteins or carb receptors on host cell and enable fusion, Ab against S protein are neutralizing, helps with survival in GI tract
epidemiology (coronavirus) isolated from human and animals, no cross infection, re-infection by same serotype possible, transmission by droplets (mostly) and some fecal oral
pthogenesis (coronavirus) optimal replication in ciliated nasal epithelium, rest unclear because no good animal model
HPIV laryngotracheobronchitis (croup), bronchitis, bronchiolitis, family paramyxoviridae, enveloped, glycoprotein with hemagglutinin & neuraminidase activity,fusion factor, ss- sense RNA, replicates in cytoplasm, fusion=release of nucleocapsid in cytoplasm
Fusion factor (F3) enables fusion of virus and host cell membranes, Ab against F protein are neutralizing
HN activity mediates infection by binding neuraminic acid containing molecule on host cell surface
pathogenesis (HPIV) V proteins (fusion proteins) prevent apoptosis, alter cell cycle, inhibit double stranded RNA signaling, prevent interferon biosynthesis
Epidemiology (HPIV) all age groups, range of respiratory syndromes from mild cold like to pneumonia
Respiratory syncytial virus (RSV) family paramyxoviridae, enveloped, helical nucleocapsid, virally enclosed surface proteins, fusion factor (G glycoprotein: attachment), no glycoprotein with HN activity, ss- sense RNA, replicates in cytoplasm
epidemiology (RSV) main cause of serious LRTI, main cause of hospitalization for RTI, main organism for bronchiolitis in children <1 yr (>81%), >50% pneumonia in children <1 yr, seasonal
pathogenesis (RSV) entry via epithelium of nose and eye, self inoculation through droplets on hand, F&G proteins mediate attachment, replicate in nasopharyngeal epithelium, localized infection, no viremia
spread (RSV) after 2-5 days spreads to LRT, causes bronchiolar epithelium necrosis, destruction of ciliated epithelial cells, infiltration of lymphocytes and mononuclear cells. Disesae enhanced when children are vaccinated using heat killed vaccine
Influenza actue influenza, family orthomyxiviridae, division into A, B, and C based on nucleocapsid and matrix proteins, enveloped, helical nucleocapsid, 2 surface glycoproteins (H and N (not in C)), ss- segmented RNA, replicates in nucleus
subgrouping of influenza A hemagglutinin and neuraminidase (see next 2 slides)
Hemagglutinin (influenza A) rod/spike shaped, 25% of viral protection, major Ag against which neutralizing Ab directed, 4 subtypes (HA1-3, 5), requires cleavage to be active: carried out by cellular proteases in nucleus
Neuraminidase (influenza A) mushroom like tetramer with slender stalk, sailidase enzyme:removes terminal sialic acid residues from glyoproteins& glycolipids. Enables release of budding virus from host cells, helps virus move through mucin layer for attachment. 2 subtypes
Influenza A very severe, animal reservoir, pandemics, epidemics, antigenic shift and drift
Influenza B Severe, no animal reservoir, no pandemics, epidemics, antigenic drift
Influenza C mildly severe, no animal reservoir, no pandemics, no epidemics, antigenic drift
Pathogenesis (influenza) attaches to sialyloligosaccharide, established primary infection in URT, NA cleaves mucus and allows attachment, replicates in columnar epithelial cells, HA mediates fusion via RME, mature virus released apically and spreads cell to cell
genetic variability segmented RNA genome susceptible to mutation and can undergo recombination
Antigenic drift can involve H or N Ag and genes encoding non-structural proteins, may be due to single mutation, selective pressures, frequently occurs in A (somtimes in B and C)
Antigenic shift sudden, major change in H or N (>50% altered),causes epidemics/pandemics,due to genetic reassortment, can occur in animal reservoirs, new subtype, little/no immunity in population
treatment (influenza) amantadine and rimantadine (prophylaxis for type A) olsetamivir (neuraminidase inhibitor, types A and B) prevention (trivalent vaccine: live attenuated, inactivated subvirion, or surface Ag)
Streptoccoci gram+, non-motile, non-spore forming, catalast negative, fermetative metabolism, anaerobic, lipoteichoic acid and polysaccharide in cell wall, many virulence factors, cultured on blood agar, sensitive to optochin and bacitracin
streptoccocus pyogenes pharyngitis, group A, beta hemolytic, bacitracin sensitive, optochin resistant. Causes scarlet fever, acute glomerulonephritis, rheumatic fever
epidemiology (pyogenes) normal microflora in nasopharynx, main cause of bacterial pharyngitis in 2-20yr olds, droplet transmission, winter and early spring distribution
Streptococcus pneumoniae pneumonia, sinusitis, otitis media, in adults: most common cause of bacterial pneumonia, lancet shaped, in pairs, alpha hemolytic, optochin sensitive, bacitracin sensitive
epidemiology (pneumoniae) commonest cause of community acquired pneumonia, normal nasopharyngeal flora (carried by 5-70% of people), no animal/environmental reservoir
Pathogenesis (pneumoniae) capsule important as virulence factor, sIgA protease, pneumolysin and autolysin, can take up DNA through transformation
pneumolysin thiol activated pore forming toxin, binds to cholesterol, released following lysis of bacteria when exposed to autolysin. Inhibits ciliated epithelial cell activity, cytotoxic for alveolar and endothelial cells, causes inflammation, decreased PMN effect
autolysin when activated breaks peptide cross linking of PG enabling pneumolysin release. Causes release of cell wall fragments, triggering an inflammatory response, contributes to pathogenesis
Prevention (pneumoniae) Ab against capsule=protective polyvalent capsular polysaccharide vaccine, recommended for young/old, those with chronic disease, HIV,and alcoholics
Antibiotic resistance (pneumoniae) penicillin usually drug of choice, resistance is due to alterations in PBP resulting in a reduced affinity for beta lactam antibiotics
Corynebacterium diptheriae diptheria, gram+, pelomorphic rods, 4 biotypes, facultative anaerobe
epidemiology (diptheriae) unusual in developed countries due to vaccine, less than 10 per year in US, endemic in some subtropical and tropical countries
pathogenesis (diptheriae) non invasive organism does not enter blood stream, exotoxin is main virulence factor, inflammation and formation of a pseudomembrane, organ damage
lad identification (diptheriae) culture (black shiny colonies on tinsdale agar: selective for K tellurite and differential for cystinase activity) and detection of toxin (PCR or Elek test: demonstrates toxin production). Both are necessary
Haemophilus influenzae otitis media, pneumonia, epiglottitis, gram-, pleomorphic, facultative anaerobe, normal in URT flora, serotyped by capsule (a-f), type b associated with invasive disease, nontypable strain carried by 50-80% of people
epidemiology (influenzae) sporadic, human pathogen, no animal/environmental reservoir, introduction of Hib vaccine has changed the profile of serotypes involved in disease
Pathogenesis (influenzae) pili, non-pilus adhesins, LPS (impairs ciliary function), antiphagocytic capsule made of PRP, IgA proteases (more than 30)
lab identification (influenzae) coagulase negative, catalast positive, chocolate agar or agar with X and V growth factors (X acts as hemin, V is NAD)
prevention (influenzae) Hib vaccine, immunity correlated with Ab against PRP capsule, vaccine made of PRP coupled to a protein carrier, mediated T cell dependent response
Bortadella pertussis pertussis, gram- coccobacillus, small
epidemiology (pertussis) may be reemerging, typically occurs in unvaccinated kids and adults whose vaccines have waned, adults are important reservoir, highly communicable via aerosols, 90%of those exposed become infected
pathogenesis (pertussis) bacterium is non-invasive, attaches to ciliated epithelia of bronchi and trachea via pili, Fha (agglutinates RBC, attaches to galactose N-acetylglucosamine residues of host cell glycolipids), and pertussis toxin.
toxins in pertussis Pertussis toxin (ADP ribosylator, targets G proteins, PT), adenylate cyclase/hemolysins toxin (ACT), tracheal cytotoxin(TCT), lipooligosaccharide (LOS), dermonecrotic toxin (DNT)
phases of pertussis (whooping cough) incubation: asymptomatic, 1 wk catarrhal: non-specific, 10d-2wk paroxysmal: characteristic signs (5-10 repeated coughs in 1 exhalation, staccato attacks, vomiting) convalescent
lab identification (pertussis) nasopharyngeal swab or secretion (not cotton swab), culture (100% specific), chocolate agar with cephalosporin, PCR
prevention (pertussis) DaPT vaccine (sP=acellular pertussis), whole cell vaccine (formalin inactivated), inactivated PT+acellular components (can decrease over time, booster shots necessary)
Kelbsiella pneumoniae severe bronchopneumonia, chronic desrtuctive lung abscess, family enterobacteriaecae, gram-, non motile, large capsule (uronic and pyruvic acid), microbial flora (in 5% of healthy individuals), high affinity iron uptake systems (aerobactin&enterochelin)
Features of lung abscesses (klebsiella) >1 area of lung parenchyma replaced by cavities filled with debris, usually polymicrobial, leads to rotting of lungs (putrid odor to breath and sputum), redcurrent jelly sputum
Legionella pneumophilia legionaire's disease, pontiac fever, gram- rods, single polar flagellum, no capsule, maybe a slime layer
epidemiology (legionella) in freshwater environments as parasite of free living amoebae, can be sequestered in biofilms, exposure by inhalation of bacilli in aerosols (air conditioning, showers), immunocompromised, elderly, males, smokers, & those with chronic bronchitis at risk
pathogenesis (legionella) facultatively intracellular, uptake via phagocytosis, survival due to prevention of phagosome acidification and blocking phagosom-lysosome fusion, damage due to host inflammatory response, virulence factors
lab identification (legionella) culture on BYCE or suitable agar, identification to genus level sufficient, demonstrate organisms or compounds, demonstrate significant levels of Ab
Mycobacterium tuberculosis TB,large, acid fast, highly contagious, aerobic, has peptidoglycan, mycolic acids, and LAM
peptidoglycan (TB) similar to gram+ bacteria, NAM and NAG cross linked via L-alanyl-D-isoglutamiyinyl meso-diaminopimelyl D-alanine tetrapeptides
Mycolic acids (TB) high moecular weight, make 60% of cell weight, slow growth and formation of clumps and cords, resist detergents, hydrophobic, extend survival
LAM (TB) similar to O Ag LPS, induces cytokine production by macrophages, suppresses T cell proliferation, inhibits IFN gamma activation of macrophages, interacts with dendritic cells to enable uptake and entry
Epidemiology (TB) 1/3 to 1/2 of worlds population carries latent infection, many are HIV related, minimum infective dose=10 bacilli, risk elevated by defects in cell mediated immunity, HIV patients have shorter duration between infection and disease
pathogenesis (TB) intrcellular survival in alveolar macrophages, prevent oxidative burst& inhibit phagosome-lysosome fusion (sulfolipids), resist lysosomal enzymes& ROI (cell wall lipid, LAM, superoxide dismutase),escape into cytoplasm, iron acquisition through siderophore
lab identification (TB) culture on lowenstein-Jensen agar or olein acid, Zeihl-Neesen stain, PPD: intradermal injection, measure diameter (>5: HIV, >10: healthcareworkers,those in institutions, >15:everyone)
Prevention (TB) prophylactic antimycotics after exposure, reduce overcrowding and poverty, BCG vaccination
Primary fungal pathogens-shared features acquired by inhalation of soil and decaying organic matter, frequently asymptomatic or mild, endemic to certain geographical areas, clinical presentation depends on level of exposure and immunologic status, dimorphic
pathogenesis of endemic mycoses inhaled-->reach terminal bronchi-->convert to form capable of replication-->colonize respiratory mucosa components of cell wall may be important
diagnosis of fungal pathogens sputum, BAL, transtracheal aspirate, lung biopsy, direct microscopy, culture on appropriate media, nucleic acid probes, fixed specimens, delayed hypersensitivity skin tests (coccidiodin-mycelial phase Ag, Spherulin-spherule phase Ag), exoantigen test
Histoplasma Capsulatum histoplasmosis, primary pathogen, 2 significant varieties (capsulatum and duboisii)
capsulatum capsulatum pulmonary and disseminated, infections, eastern US Mexico central and South America, thinner cell walls, smaller size
capsulatum duboisii skin and bone lesions, tropical Africa, thicker walled, larger yeasts
epidemiology (histoplasma) natural habitat: saphrophyte in most rich soils with high N2 content (bird/bat feces), old decaying buildings, areas of demolition or reconstruction
pathogenesis (histoplasma) facultative intracellular pathogen in monocyte (survival=pH mod),infection by inhalation,can disseminate via liver, spleen,contained by cell mediated immune response,can detect using skin DTHR, persistent subclinical infection with subsequent reactivation
Blastomyces dermatidis primary pathogen, blastomycosis, mycelium: branching, septate; yeasts:oval to round
epidemiology (blastomyces) similar geographic distribution to histoplasmosis, infection due to inhalation of condida and hyphal fragments, leads to cutaneous infection (primary or secondary), or systemic infection (sublcinical, acute primary pulmonary, chronic pneumonia, systemic)
Coccidiodes coccidioidomycosis
epidemiology (coccidioidomycosis) exposure through inhalation of hyphal arthroconidia, in arid and semi-arid soils, highest exposure in late summer/early fall and in dry seasons preceded by rainfall. California (immitis) other places (posadasii)
pathogenesis (coccidioidomycosis) inhalation of arthroconidia-->primary coccidioidomycosis, convert to large spherule (size prevents phagocytosis), filled with endospores
outcomes (coccidioidomycosis) asymptomatic/mild (60%),flu like (40%), mostly self limiting, can progess to chronic fibrocavitary disease or disseminated disease to any tissue/organ Recovery depends on T-lymphocyte response
other endemic mycoses paracoccidioidomycosis (south american blastomycosis) acute/subacute (juvenile), chronic (adult, or opportunistic. Large yeast with multiple buds "ships wheel"
opportunistic fungal pathogens monomorphic, acquired via inhalation, cause of disease in immunocompromised, same lab diagnosis as other fungi
immunocompromised and fungal infections chemotherapy (aspergillus pneumocystis), assisted ventilation (aspergillus), malnutrition (pneumocystis, C. neoformans), HIV/AIDS (C. neoformans, pneumocystis), Neutropenia (aspergillus and others)
Cryptococcus neoformans cryptococcosis, encapsulated yeast in tissue, unencapsulted in environment
epidemiology (cryptococcus) worldwide distribution, grows well in soil enriched by pigeon droppings, most common fungal infection seen in AIDS
pathogenesis (cryptococcus) inhalation of unencapsulated yeasts into alveoli triggers production of capsule (GXM, detectable in blood and fluids, down regulates the immune response), has strong affinity for CNS, can oxidize exogenous catecholamines to melanin
Pneumocystis Jiroveci pneumocystis pneumonia, lacks ergosterol in cell wall, difficult to grow in culture
epidemiology (jiroveci) worldwide, may or may not be person to person transmissible, low level of infectivity (need to be immunocompromised)
Aspergillus Aspergillosis (fumigatus, flavus, niger)
epidemiology (aspergillus) worldwide, found in decaying matter, soil, and air, causes allergic aspegillosis or invasive aspergillosis (fungal ball)
Hantavirus hantavirus pulmonary syndrome, severe pulmonary distress, pneumonia, high mortality, ss- RNA, 3 segments (S,M,L), reservoir: long tailed pygmy rice rats (chile), rats and mice (US), infection by inhalation of excreta. Emerging.
Metapneumovirus bronchiolitis, recently recognized, seems to be widespread, RT-PCR needed for diagnosis
otitis media earache, fever, discharge, irritability, vomiting, diarrhea. Various bacterial causes
sinusitis nasal congestion, purulent discharge, pain over affected area. Due to various bacteria
conjunctivitis redness, discharge, irritation. Due to various viruses and bacteria
common cold sneezing, rhinorrhea, blocked nose, mild sore throat, headache, malaise. Rhinoviruses and coronaviruses
Pharyngitis and tonsilitis sore scratchy throat, exudate on tonsils. Adenoviruses, strep pyogenes
Laryngitis symptoms of URTI plus hoarseness, usually viral
Diptheria exudative pharyngitis, sore throat, low grade fever and malaise, pseudomembrane, C. diptheria
Acute bronchitis symptoms of RTI, productive cough. Due to various organisms
Whooping cough Cararrhal phase:rhinorrhea, sneezing, malaise, fever, anorexia. Paroxysmal phase:repetitive coughing with whoops, vomiting, leukocytosis. Due to B. pertussis
Croup Mild upper RTI, fever, noisy respiration, barking. Due to HPIV
Bronchiolitis fever, wheezing, tachypnea, rales. Due to RSV, HPIV
Influenza fever, malaise, myalgia, sore throat, nonproductive cough, rhinorrhea, sneezing. Due to influenzaviruses
TB fever, malaise, weight loss, night sweats, hemoptysis. Due to M. tuberculosis
Acute pneumonia fever, general feeling of sickness, chest pain, cough, shortness of breath, rapid respiration, shadowy infiltrate on chest XRay. Due to various organisms
Chronic pneumonia mild: fever and cough more severe: chills, malaise, fever, chest pain, sputum production, weight loss, granulomatous lesions. Due to endemic and opportunistic fungi
Created by: kamarsh



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